What is going on in the drug and device industry? Hardly a month goes by without a medication or medical device being identified as having dangerous side-effects, the Food and Drug Administration (FDA) holding hearings, lawyers taking out ads looking for victims, class-action suits getting filed, or patients being left to talk with their equally confused doctors about whether they should stop treatment given the newly identified deaths, risks, recalls, or warnings. Aren’t we supposed to have a regulatory system in the United States that gives drugs, vaccines, and devices a rigorous assessment before releasing them into the marketplace?
The answer is that we have a regulatory system that is too skewed toward looking at the earliest stages of research. Moreover, it is designed so that disaster is almost an inevitable result of the way evidence is collected on new products.
Why? At a time when the cost of health care continues to spiral out of control, with drug prices leading the way, why are we “treated” to case after case after case of an FDA-approved drug or medical device getting yanked—amidst pharmaceutical company executives’ howls of protest and lawyers’ suppressed giggles of glee? The diabetes drug Avandia is the latest in the long, bizarre, and expensive parade of drugs that failed well after their approval by the FDA. Sales of Avandia (rosiglitazone) began to fall after a 2007 study suggested that it could cause heart attacks and strokes. The FDA then put a black-box warning on Avandia telling physicians to be aware of the heart-attack risk. This put the uncertainty squarely in the laps of diabetes patients.
Earlier this year, the pharmaceutical giant GlaxoSmithKline plc (GSK) settled thousands of lawsuits with patients who claimed that Avandia caused them to have heart attacks. GSK had already settled approximately seven hundred cases in the United States for around sixty million dollars. The company faces the possibility of paying billions more to those claiming to have been harmed.
This year, even more evidence appeared that questioned Avandia’s safety and suggested GSK might have withheld data that would have pointed out the problems. The FDA appointed an advisory panel in July to consider the latest allegations. That panel was quickly caught up in charges that a few of its most vigorous defenders of the diabetes drug may have been on the Glaxo payroll!
Avandia follows hard on the heels of PREMPRO, a hormone replacement therapy made by Wyeth that is caught up in lawsuits alleging it caused breast cancer. PREMPRO followed hard on the heels of the recall of Medtronic’s Sprint Fidelis defibrillator, a recall that was preceded by Merck’s recall of Vioxx, which came after problems with Abbott’s Meridia, Pfizer’s Rezulin, Bayer’s Baycol, Guidant’s VENTAK defibrillators, Boston Scientific’s Express stent, and, and, and—well, you get the idea.
So what is wrong with the oversight of new drugs and devices? Why are there so many recalls, scandals, and warnings even after FDA approval?
The major problem behind this mess is that drug and device regulation is heavily weighted in the United States toward the early stages of research. Every drug has to be tried in animals to determine safety. Then drugs are introduced into a small number of humans to check safety—the Phase 1 trials. Dose and mode of administration are checked for safety, biological activity, and signs of effectiveness—this is Phase 2. Only after all this safety testing is a drug or device ready to go to clinical trials in hundreds or sometimes thousands of subjects—the Phase 3 study, which takes place almost always in a placebo-controlled, randomized, blinded trial. It is as if the regulatory system wants to do all it can to protect human subjects from getting harmed at the earliest stages of research. The deaths of subjects like Ellen Roche and Jesse Gelsinger in early-stage studies over a decade ago reinforced regulatory anxiety about deaths in initial human studies.
Meanwhile, the last stage of research—Phase 4, in which drugs are to be monitored for adverse events and problems while in actual use out in the world—is the weakest link. Drug companies sometimes promise to do these trials to get final product approval but then don’t bother. Reporting is left to doctors and patients, who do so rarely. There is no systematic tracking of subpopulations to see what is going on with real patients in real-world conditions. Deaths need to mount rapidly and obviously to get regulatory attention.
In addition, testing drugs and devices in randomized, blinded, placebo-controlled trials is great, but it means that approval is given on the basis of highly controlled studies in highly selective populations—often subjects who are not terribly old, not particularly sick, and who furthermore tend to be highly compliant with dosage regimens. This is not the story in the real world, where patients take lots of drugs—some legal, some not—are poorly compliant, have multiple diseases, and can be very old or very young. A drug that looks safe in a Phase 2 or 3 study can prove lethal when given to real people in uncontrolled, unsupervised environments.
Ethically, the parade of horrors that marches across the media in news accounts of drugs gone bad merits a reexamination of a regulatory system that is not keeping us safe. The issue is not “too much bureaucracy and too much red tape,” but a strategy of safety that puts emphasis in the wrong places instead of dealing with the realities of prescription medicine usage.